Osmotic delivery system flow modulator apparatus and method

ABSTRACT

An osmotic delivery system flow modulator assembly, an osmotic delivery system with a flow modulator assembly, and a method of assembling an osmotic delivery system. The osmotic delivery system flow modular assembly includes a body having a hole located through the body and communicating two opposing ends of the body. The use of the osmotic delivery system flow modulator assembly lessens the chance that air or gas pockets will form in the enclosure of the osmotic delivery system during assembly of the system. Because less air is within the osmotic delivery system, performance of the system is enhanced. Use of the flow modulator assembly also lessens the chance that beneficial agent will be wasted during assembly of the osmotic delivery system.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/053,690 filed Jul. 25, 1997, pursuant to 35 U.S.C. §119(e).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to osmotic delivery systems for deliveringbeneficial agents, and more particularly, to an osmotic delivery systemflow modulator.

2. Description of the Related Art

Controlled delivery of beneficial agents, such as drugs, in the medicaland veterinary fields is accomplished by a variety of methods. Onemethod of controlled prolonged delivery of beneficial agents involvesthe use of osmotic delivery systems. These devices can be implanted torelease beneficial agents in a controlled manner over a pre-selectedtime or administration period. In general, osmotic delivery systemsoperate by imbibing fluid from the outside environment and releasingcorresponding amounts of the beneficial agent.

Osmotic delivery systems, commonly referred to as “osmotic pumps,”generally include some type of a capsule or enclosure having a wallwhich selectively permits liquid to enter the interior of the enclosurewhich contains a liquid attracting osmotic agent. The absorption ofliquid by the osmotic agent within the enclosure creates osmoticpressure within the enclosure which, in turn, causes the beneficialagent to be delivered from the enclosure. The osmotic agent may be thebeneficial agent and/or a formulation containing the same delivered tothe patient. However, in many cases, a separate osmotic agent is usedspecifically for its ability to draw liquid into the enclosure.

When a separate osmotic agent is used, the osmotic agent may beseparated from the beneficial agent within the osmotic delivery systemenclosure by a dividing member or movable piston. The structure of theosmotic delivery system does not permit the enclosure to expand when theosmotic agent takes in water and swells. As the osmotic agent expands,it causes the beneficial agent to be discharged through an orifice ordelivery port in the enclosure at generally the same rate as a liquid,which is typically water, enters the osmotic agent by osmosis. Osmoticdelivery systems may be designed to deliver a beneficial agent at acontrolled constant rate, a varying rate, or in a pulsatile manner.

In some known osmotic delivery systems, the osmotic agent is typicallyshaped as an osmotic tablet, and is placed inside the enclosure. Asemipermeable membrane plug is then typically placed in an opening inthe enclosure through which the tablet was inserted. The semipermeablemembrane plug acts as the wall which selectively permits liquid to enterthe interior of the enclosure. Known semipermeable membrane plugs aretypically a cylindrical member with ribs, and operate in the same manneras a cork. These semipermeable membrane plugs seal the interior of theenclosure from the exterior environment of use, only permitting certainliquid molecules from the environment of use to permeate through thesemipermeable membrane plug into the interior of the enclosure. The ratethat the liquid permeates through the semipermeable membrane plugcontrols the rate at which the osmotic agent expands and drives adesired concentration of beneficial agent from the delivery systemthrough the delivery port. Osmotic delivery systems may control the rateof delivery of the beneficial agent by varying the permeabilitycoefficient of the semipermeable membrane plug.

In known osmotic delivery systems, the beneficial agent exits theosmotic delivery system enclosure through a delivery port. Such deliveryports are typically fashioned in a plug-like member which is insertedinto an opening of the osmotic delivery system enclosure. The opening ofthe enclosure into which the delivery plug is inserted is typicallyopposite the end of the enclosure which holds the semipermeable membraneplug. Thus, in assembling these osmotic delivery systems, the dividingmember is first inserted into the enclosure. Then the osmotic agent oragents are inserted into the enclosure, and the semipermeable membraneplug is inserted into the opening through which the dividing member andosmotic agents where inserted. Thereafter, if the osmotic deliverysystem enclosure includes two openings located opposite from each other,the system is rotated 180°, and the beneficial agent is inserted intothe enclosure through the opening through which the delivery plug is tobe inserted. After the desired amount of beneficial agent has beeninserted into the enclosure, the delivery plug having the delivery portis then inserted into the opening through which the beneficial agent wasinserted. The delivery plug effectively seals the enclosure from theexterior environment, except for the delivery port.

When the osmotic delivery system with the delivery plug is placed in theenvironment of use, liquid is imbibed through the semipermeable membraneplug by osmosis, causing the osmotic agent to expand and causing thebeneficial agent to flow through the delivery port in the delivery plug.Thus, the beneficial agent exits the enclosure of the osmotic deliverysystem through the delivery port, and is delivered to the environment ofuse.

One problem associated with the above-described osmotic delivery system,is that air or gas is frequently trapped above the beneficial agent asthe delivery plug is inserted into the osmotic delivery systemenclosure. When liquid begins to be imbibed by the osmotic agent throughthe membrane plug, the osmotic agent expands and drives the dividingmember, compressing the beneficial agent to be delivered through thedelivery port. Because of air pockets trapped in the compartment orwithin the beneficial agent formulation itself, the osmotic pressuremust compress the air pockets before the incompressible beneficial agentwill be delivered through the delivery channel in the delivery plug.This is problematic because the start-up period to delivery of thebeneficial agent is delayed by the amount of time during which the airpockets are compressed. The time to “start-up” of delivery generallyrefers to the time from insertion into the environment of use until thebeneficial agent is actually delivered at a rate not less thanapproximately 70% of the intended steady-state rate. The start-up periodmay be delayed up to several days or weeks, depending upon the size ofthe air gaps and the flow rate of the system. Delayed start-up ofbeneficial agent delivery is a significant problem in osmotic deliverysystems. Furthermore, air might be expelled from the osmotic deliverysystem and cause serious health risks to, for example, humans havingimplanted osmotic delivery systems, depending on where the system isimplanted.

If the osmotic delivery system includes a delivery plug with a verysmall delivery path or channel, the trapped air may completely preventthe flow of beneficial agent from the delivery channel and/or cause thebeneficial agent to be delivered in sporadic bursts.

Another problem associated with the above-described osmotic deliverysystem is that surplus beneficial agent is typically expelled from theenclosure when the delivery plug is inserted into the enclosure whichcontains the beneficial agent. Surplus beneficial agent is necessary toensure that as much air as possible escapes the delivery enclosure. Thisexpelled beneficial agent must be cleaned from the osmotic deliverysystem enclosure, and makes it difficult to precisely determine theamount of beneficial agent within the osmotic delivery system and theamount of beneficial agent eventually delivered. This wasted agentproblem is even more dramatic because most beneficial agents areextremely expensive, and the surplus agent cannot be recovered forre-use. In some instances, as much as forty microliters of beneficialagent may be expelled during the insertion process.

The delivery channel or orifice in the delivery plug which has beeninserted in the above-described osmotic delivery systems is the site ofinteraction between the beneficial agent and the external environment ofuse. One constraint of certain delivery paths of known delivery plugs isthat they must be small enough, either in length and/or interiorcross-sectional area, such that the average velocity of active agent outof the delivery system enclosure is higher than the inward flow ofliquid into the delivery system from the environment of use. Thus, thesedelivery channels or orifices in the delivery plug serve the importantfunction of isolating the beneficial agent from liquids and particulatein the external environment of use, since any contamination of thebeneficial agent by such external substances may adversely affect theutility of the beneficial agent. For example, the inward flux ofmaterials from the environment of use due to diffusion through thedelivery orifice may contaminate the interior of the capsule,destabilizing, diluting, or otherwise altering the beneficial agentformulation. It has been particularly problematic to prevent thediffusion of liquids from the environment of use through the deliveryorifice of known osmotic delivery systems such that the utility of thebeneficial agent is not impaired, while also obtaining the desireddelivery rate of beneficial agent from the osmotic delivery system.

Still another problem associated with the above-described osmoticdelivery system is that after the delivery plug has been inserted intothe enclosure of the osmotic delivery system, the end of the system withthe delivery plug inserted therein must be capped. This capping processis necessary to prevent the beneficial agent from evaporating throughthe delivery channel or orifice in the delivery plug during the periodof time before the osmotic delivery system is inserted into itsenvironment of use. Thus, during the implantation procedure, the capmust be removed prior to implantation of the unit, further complicatingthe implantation process and the assembly process of the osmoticdelivery system.

Because of the above-identified problems associated with current osmoticdelivery systems, it is costly and particularly difficult to administerbeneficial agents from osmotic delivery systems at controlled deliveryrates.

SUMMARY OF THE INVENTION

A primary object of the present invention is to provide an osmoticdelivery system flow modulator assembly which enhances performance ofosmotic delivery systems.

Another object of the present invention is to provide an osmoticdelivery system flow modulator assembly which can reduce the start-uptime before delivery of the beneficial agent from an osmotic deliverysystem.

Still another object of the present invention is to provide an osmoticdelivery system flow modulator assembly which simplifies the assembly ofosmotic delivery systems.

Another object of the present invention is to provide an osmoticdelivery system flow modulator assembly which reduces back diffusion ofsubstances from the external environment into the osmotic deliverysystem.

Yet another object of the present invention is to provide an osmoticdelivery system which has a reduced start-up time as compared toconventional osmotic delivery systems.

Another object of the present invention is to provide an osmoticdelivery system that does not require a cap on the osmotic deliverysystem after assembly to prevent beneficial agent evaporation from thesystem.

Another object of the present invention is to provide a method ofassembling an osmotic delivery system which reduces the amount of wastedbeneficial agent.

Still another object of the present invention is to provide a method ofassembling an osmotic delivery system which reduces the possibility ofgas or air trapped therein.

Another object of the present invention is to provide a method ofdelivering a beneficial agent into an osmotic delivery system whichpermits air or gas to escape the enclosure of the osmotic deliverysystem while the beneficial agent is delivered into the enclosure.

The present invention addresses the disadvantages of known osmoticdelivery systems by providing embodiments of an osmotic delivery systemflow moderator or modulator body, an osmotic delivery system flowmodulator assembly, an osmotic delivery system incorporating the flowmodulator assembly, a method of assembling an osmotic delivery system,and a method of delivering a beneficial agent into an osmotic deliverysystem. As used herein, “modulator” and “moderator” are usedinterchangeably. The osmotic delivery system flow modulator body orassembly reduces the occurrence of air pockets within the beneficialagent or between the beneficial agent and the flow modulator, reducesthe amount of beneficial agent wasted when assembling the deliverysystem, and, according to another embodiment of a flow modulatorassembly, minimizes the back diffusion of substances from the externalenvironment of use.

According to one aspect of the present invention, an osmotic deliverysystem includes a semipermeable portion, and an enclosure having anopening and an interior for holding a liquid swellable osmotic agent anda beneficial agent. The liquid swellable osmotic agent imbibes liquidfrom a surrounding environment through the semipermeable portion tocause delivery of the beneficial agent from the enclosure. Also includedis an osmotic delivery system flow modulator body at least partiallypositioned in the opening of the enclosure. The body has two opposingends and means for venting the osmotic delivery system when thebeneficial agent is inserted into the osmotic delivery system. Adelivery path is located separate from the venting means, and is fordelivering the beneficial agent from the osmotic delivery system. Thedelivery path is formed in at least one of the enclosure and the body.

According to another aspect of the present invention, an osmoticdelivery system flow modulator assembly includes a flow modulator bodyconstructed and arranged for at least partial positioning in an openingof an enclosure of an osmotic delivery system. The body includes twoopposing ends, and a vent hole located through the body communicates theopposing ends. A delivery path is formed in the body, and is locatedseparate from the hole for delivering a beneficial agent from theosmotic delivery system.

According to another aspect of the present invention, an osmoticdelivery system flow modulator assembly includes a flow modulator bodyconstructed and arranged for at least partial positioning in an openingof an enclosure of an osmotic delivery system. The body includes twoopposing ends, a first hole located through the body, and a second holelocated through the body. The first hole and the second hole eachcommunicate the opposing ends. The flow modulator body includes adelivery path for delivering a beneficial agent from the osmoticdelivery system. The flow modulator assembly includes means for sealingat least one of the first and second holes.

According to another aspect of the present invention, an osmoticdelivery system includes a semipermeable portion and an enclosure havingan opening and an interior for holding a liquid swellable osmotic agentand a beneficial agent. The liquid swellable osmotic agent imbibesliquid from a surrounding environment through the semipermeable portionto cause delivery of the beneficial agent from the enclosure. Thedelivery system includes an osmotic delivery system flow modulatorassembly having a body at least partially positioned in the opening ofthe enclosure. The body has two opposing ends, a first hole locatedthrough the body, and a second hole located through the body. The firstand second holes each communicate the opposing ends. The flow modulatorassembly includes at least one cap positioned in one of the first andsecond holes, and at least one of the body and the enclosure include adelivery path for delivering a beneficial agent from the osmotic agentdelivery system.

According to another aspect of the present invention, an osmoticdelivery system flow modulator assembly includes a body constructed andarranged for at least partial positioning in an opening of an enclosureof an osmotic delivery system. The body has two opposing ends, and ahole located through the body. The hole communicates the opposing ends.The body has a delivery path for delivering a beneficial agent from theosmotic delivery system. A stopper has a head, a shaft, and a tiplocated opposite from the head. The stopper is at least partiallypositioned in the hole to seal the hole, and a partition secured to thebody with the stopper so that the partition is secured between the bodyand the head of the stopper.

According to another aspect of the present invention, an osmoticdelivery system includes a semipermeable portion, and an enclosurehaving an opening and an interior for holding a liquid swellable osmoticagent and a beneficial agent. The liquid swellable osmotic agent imbibesliquid from a surrounding environment through the semipermeable portionto cause delivery of the beneficial agent from the enclosure. An osmoticdelivery system flow modulator body is at least partially positioned inthe opening of the enclosure. The body has two opposing ends, and a holelocated through the body communicating the opposing ends. A deliverypath is located separate from the hole and formed in at least one of thebody and the enclosure for delivering the beneficial agent from theosmotic delivery system. Also included are means for substantiallypreventing a liquid external from the osmotic delivery system fromentering the interior of the osmotic delivery system. The preventingmeans allows the beneficial agent to exit the osmotic delivery system tothe surrounding environment.

According to another aspect of the present invention, a method ofassembling an osmotic delivery system includes the steps of: positioningan osmotic agent in an interior of the enclosure; inserting an osmoticdelivery system flow modulator body at least partially in the opening ofthe enclosure to at least partially seal the opening, one of the flowmodulator body and the enclosure having a delivery path for delivering abeneficial agent from the osmotic delivery system; and delivering abeneficial agent into the enclosure through a fill hole in the flowmodulator body.

According to another aspect of the present invention, a method ofdelivering a beneficial agent into an osmotic delivery system includesthe steps of inserting the beneficial agent through a hole in a flowmodulator body inserted in an opening of the osmotic delivery system,and venting a gas from the osmotic delivery system through the holewhile inserting the beneficial agent through the hole.

According to another aspect of the present invention, a method ofassembling an osmotic delivery system includes the steps of positioningan osmotic agent into an interior of the enclosure; inserting an osmoticdelivery system flow modulator body at least partially in the opening ofthe enclosure, the flow modulator body having a hole and a delivery pathlocated separate from the hole; delivering a beneficial agent into theenclosure through the hole in the flow modulator body; and creating avacuum adjacent to the flow modulator body to reduce an amount of gaswithin the osmotic delivery system.

Still other objects and advantages of the present invention will becomereadily apparent to those skilled in the art from the following detaileddescription, which illustrates and describes the preferred embodiment ofthe present invention. As will be realized, the invention is capable ofmodification in various obvious aspects, all without departing from theinvention. Accordingly, the drawings and description are to be regardedas illustrative in nature, and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in greater detail with reference to theaccompanying drawings in which like elements bear like referencenumerals, and wherein:

FIG. 1 is a side view of an osmotic delivery system flow modulatoraccording to one embodiment of the present invention;

FIG. 2 is an end view of an osmotic delivery system flow modulatoraccording to one embodiment of the present invention;

FIG. 3 is a cross-sectional side view of the osmotic delivery systemflow modulator according to one embodiment of the present inventiontaken along the line 3—3 of FIG. 2;

FIG. 4 is a cross-sectional side view of an osmotic delivery systemaccording to one embodiment of the present invention;

FIG. 5 is an end view of an osmotic delivery system flow modulatoraccording to one embodiment of the present invention;

FIG. 6 is a cross-sectional side view of the osmotic delivery systemflow modulator according to one embodiment of the present inventiontaken along the line 6—6 of FIG. 5;

FIG. 7 is a cross-sectional side view of an osmotic delivery system flowmodulator according to one embodiment of the present invention;

FIG. 8 is a cross-sectional side view of an osmotic delivery system flowmodulator according to one embodiment of the present invention;

FIG. 9 is a cross-sectional side view of the assembly of an osmoticdelivery system according to one embodiment of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates to osmotic delivery system flow modulatorassemblies which enhance the start-up and performance of osmoticdelivery systems which incorporate the flow modulator. FIGS. 1, 6, and 8illustrate osmotic delivery system flow modulator assemblies 20, 120,220 according to embodiments of the present invention. The osmoticdelivery system flow modulator assemblies 20, 120, 220 will be describedin reference to exemplary osmotic delivery systems 40, 140, 240according to embodiments of the present invention. The osmotic deliverysystems 40, 140, 240 include the respective flow modulator assemblies20, 120, 220.

The osmotic delivery system flow modulator assemblies 20, 120, 220include a flow modulator body 21, 121, 221 having venting means or holes24, 124, 224 located through the bodies of the flow modulator assembliesand communicating the opposing ends of the bodies. The flow modulatorbody 21 also includes a second, additional hole or fill hole 22 alsocommunicating the two opposing ends 37, 38. The osmotic delivery systemflow modulator assemblies 20, 120, 220 lessen the chance that air or gaspockets will form in the enclosures 42, 142, 242 of the osmotic deliverysystems 40, 140, 240 during assembly of the system, specifically duringthe delivery of the beneficial agent 44, 144, 244 into the enclosure ofthe system through the holes 22, 124, 224. Because use of the osmoticdelivery system flow modulator assemblies 20, 120, 220 with the osmoticdelivery systems 40, 140, 240 lessens the chance of air or gasformations within the enclosures 42, 142, 242, the time to start-up ofdelivery of the beneficial agent 44, 144, 244 and performance of thesystem is enhanced. Use of the flow modulator assemblies 20, 120, 220also lessens the chance that beneficial agent 44, 144, 244 will bewasted during assembly of the osmotic delivery systems 40, 140, 240.

FIG. 1 illustrates a side view of the exemplary osmotic delivery systemflow modulator assembly 20. The body 21 of the flow modulator assembly20 is constructed and arranged for at least partial positioning in thesecond opening 39 of the enclosure 42. The flow modulator body 21illustrated in FIGS. 1-4 is generally cylindrically shaped, and isintended for insertion or positioning into the second opening 39 of theenclosure 42 of the exemplary osmotic delivery system 40. Because theenclosure 42 and opening 39 therein are cylindrical, the flow modulatorbody 21 is also cylindrical such that it is at least partiallypositionable in the second opening of the enclosure. Of course, the flowmodulator body 21 may be other different shapes and sizes, whichgenerally correspond to that of the second opening 39 in the enclosure42 of the osmotic delivery system 40, such that the body 21 of the flowmodulator assembly 20 is constructed and arranged for at least partialpositioning in the opening. For example, if the second opening 39 of theenclosure 42 were square, the flow modulator would also be configured ina square shape.

The osmotic delivery system flow modulator body 21 is formed from aninert and, preferably, biocompatible material. Exemplary biocompatibleand inert materials include, but are not limited to, metals such astitanium, stainless steel, platinum and their alloys, andcobalt-chromium alloys and the like. Other compatible materials includepolymers such as polyethylene, polypropylene, polycarbonate,polymethylmethacrylate, and the like.

As illustrated in FIG. 1, the flow modulator body 21 of the osmoticdelivery system flow modulator assembly 20 may include the delivery path32. In the embodiment of the present invention illustrated in FIG. 1,the delivery path 32 is helical shaped. This helical delivery path 32permits the beneficial agent 44 located within the enclosure 42 of theosmotic delivery system 40 to travel from the interior of the enclosureto the exterior environment of use. The helical delivery path 32 isformed between the threads 36 which are located on the elongated portionof the osmotic delivery system flow modulator body 21.

Once the flow modulator body 21 is inserted into the second opening 39of the enclosure 42 above the beneficial agent 44, the interior surface43 or wall of the enclosure will abut against the threads 36 such thatthe only area through which the beneficial agent may travel is thedelivery path 32 formed between the threads. So configured, the helicaldelivery path 32 begins at the delivery entrance 28 which intersects thefirst opposing end 37, and ends at the delivery orifice 30. Once theosmotic agent 47 generates osmotic pressure within the delivery system,the beneficial agent 44 within the enclosure 42 will travel into thedelivery entrance 28, flow along the helical delivery path 32, andfinally exit the delivery orifice 30 to the environment of use.

The pitch, the amplitude, cross-sectional area, and the shape of thehelical path 32 formed between the abutting surfaces of the threads 36and the interior surface 43 of the enclosure 42 are factors that affectboth the back pressure within the osmotic delivery system 40 and thepossibility of back diffusion through the delivery path 32. In general,the geometry of the delivery path 32 is such that it reduces backdiffusion of liquid from the environment of use into the enclosure 42.However, as further described below, a flow modulator assembly 120according to another embodiment of the present invention may be used tomechanically minimize back flow or back diffusion. The geometry of theosmotic delivery system flow modulator body 21 illustrated in FIG. 1 issuch that the length of the helical flow path 32 and the velocity offlow of beneficial agent 44 therethrough is sufficient to prevent backdiffusion of external liquid through the flow path 32 withoutsignificantly increasing the back pressure within the enclosure 42.Thus, following start-up of the osmotic delivery system 40, the releaserate of the beneficial agent 44 is governed by the osmotic pumping rateof the system. Factors to be considered in sizing the delivery path 32are disclosed in U.S. patent application Ser. No. 08/595,761, the entiredisclosure of which is incorporated herein by reference.

The size of the flow modulator body 21 is such that a seal is formedbetween the interior surface 43 of the enclosure 42 and the outersurface of the threads 36 on the flow modulator body 21. The seal formedbetween the modulator 20 and the enclosure 42 preferably may withstandthe maximum osmotic pressure generated within the osmotic deliverysystem 40, or to fail safe if the pressure within the system exceeds apredetermined threshold. In the embodiment of the present inventiondepicted in FIGS. 1-4, the flow modulator fits tightly into the secondopening 39 of the enclosure 42, forming a seal between the threads 36 ofthe body 21 and the inner surface 43 of the enclosure. However, the sealmay be formed by other techniques well known in the art.

The delivery path 32 of the beneficial agent 44 is formed between thethreads 36 of the modulator 20 and the enclosure 42. The delivery pathlength, interior cross-sectional shape, and area of the path are chosensuch that the average linear velocity of the beneficial agent 44 throughthe path is higher than that of the linear inward flux of materials inthe environment of use due to diffusion or osmosis, thereby attenuatingor moderating back diffusion and its deleterious effects ofcontaminating the interior of the osmotic delivery system 40,destabilizing, diluting, or otherwise altering the beneficial agentformulation. The release rate of the beneficial agent 44 can be modifiedby modifying the delivery pathway 32 geometry, as described below.

The convective flow of beneficial agent 44 out of the delivery orifice30 is set by the pumping rate of the osmotic delivery system 40 and theconcentration of beneficial agent in the enclosure 42, which can berepresented as follows:

Q _(ca)=(Q)(C _(a))  (1)

where

Q_(ca) is the convective transport of beneficial agent 44 in mg/day

Q is the overall convective transport of the beneficial agentformulation in cm³/day

C_(a) is the concentration of beneficial agent 44 in the formulationwithin enclosure 42 in mg/cm³

The diffusive flow of agent 44 through the delivery orifice 30 is afunction of agent concentration, cross-sectional configuration ofdelivery path 32, agent diffusivity, and length of delivery path, whichcan be represented as follows:

Q _(da) =Dπr ² ΔC _(a) /L  (2)

where

Q_(da) is the diffusive transport of agent 44 in mg/day

D is the diffusivity through the delivery path 32 in cm²/day

r is the effective inner radius of the delivery path in cm

ΔC_(a) is the difference between the concentration of beneficial agent44 in the enclosure 42 and in the environment of use outside of thedelivery orifice 30 in mg/cm³

L is the length of the delivery path in cm

In general, the concentration of beneficial agent 44 in the enclosure 42is much greater than the concentration of agent in the environment ofuse such that the difference, ΔC_(a) can be approximated by theconcentration of agent within the enclosure, C_(a). Thus:

Q _(da) =Dπr ² C _(a) /L  (3)

It is generally desirable to keep the diffusive flux of agent at lessthan 10% of the convective flow. This is represented as follows:

Q _(da) /Q _(ca) =Dπr ² C _(a) /QC _(a) L=Dπr ² /QL≦0.1  (4)

Equation 4 indicates that the relative diffusive flux decreases withincreasing volumetric flow rate and path length, increases withincreasing diffusivity and channel radius, and is independent ofbeneficial agent concentration.

The diffusive flux of water where the orifice 30 opens into theenclosure 42 can be approximated as:

Q _(wd)(res)=C _(o) Qe ^((−QL/DwA))  (5)

where

C_(O) is the concentration profile of water in mg/cm₃

Q is the mass flow rate in mg/day

L is the length of the delivery path in cm

D_(w) is the diffusivity of water through the material in the deliverypath in cm²/day

A is the cross-sectional area in the delivery path in cm²

The hydrodynamic pressure drop across the delivery orifice can becalculated as follows: $\begin{matrix}{{\Delta \quad P} = \frac{8{QL}\quad \mu}{\pi \quad r^{4}}} & (6)\end{matrix}$

Simultaneously solving equations (4), (5) and (6) gives the values shownin Table 1 for a series of different effective delivery orificediameters where:

Q=0.38 μl/day

C_(a)=0.4 mg/μl

L=5 cm

D_(a)=2.00 E-06 cm²/sec

μ=5.00 E+02 cp

C_(wo)=0 mg/μl

D_(w)=6.00 E+06 cm²/sec

TABLE 1 Drug Diffusion & Pumping Pressure Effective Pump Rate DiffusionWater Intrusion Drop Orifice dia Cross Sec Q_(ca) Q_(da) Diff/ConvQ_(dw) Q_(dw) delta P (mil) area (mm2) mg/day mg/day Q_(da)/Q_(ca)mg/day mg/year psi 1 0.00051 0.152 0.0001 0.0005 0 0 1.55800 2 0.002030.152 0.0003 0.0018 1.14E−79 4.16E−77 0.09738 3 0.00456 0.152 0.00060.0041 4.79E−36 1.75E−33 0.01923 4 0.00811 0.152 0.0011 0.0074 8.89E−213.25E−18 0.00609 5 0.01267 0.152 0.0018 0.0115 1.04E−13 3.79E−11 0.002496 0.01824 0.152 0.0025 0.0166 7.16E−10 2.61E−07 0.00120 7 0.02483 0.1520.0034 0.0226 1.48E−07 5.4E−05 0.00065 8 0.03243 0.152 0.0045 0.02954.7E−06 0.001715 0.00038 9 0.04105 0.152 0.0057 0.0373 5.04E−05 0.0183810.00024 10 0.05068 0.152 0.0070 0.0461 0.000275 0.100263 0.00016 110.06132 0.152 0.0085 0.0558 0.000964 0.351771 0.00011 12 0.07298 0.1520.0101 0.0664 0.002504 0.913839 0.00008 13 0.08564 0.152 0.0118 0.07790.005263 1.921027 0.00005 14 0.09933 0.152 0.0137 0.0903 0.009493.463836 0.00004 15 0.11402 0.152 0.0158 0.1037 0.015269 5.5731950.00003 16 0.12973 0.152 0.0179 0.1180 0.022535 8.225224 0.00002 170.14646 0.152 0.0202 0.1332 0.031114 11.35656 0.00002 18 0.16419 0.1520.0227 0.1493 0.040772 14.88166 0.00001 19 0.18295 0.152 0.0253 0.16640.051253 18.70728 0.00001 20 0.20271 0.152 0.0280 0.1844 0.06230922.7427 0.00001

In the embodiment of the flow modulator 20 illustrated in FIG. 1, thedelivery path 32 may be between about 0.5 and 20 cm long, preferablybetween about 1 and 10 cm long and between about 0.001 and 0.020 inchesin diameter, preferably between about 0.003 and 0.015 inches to allowfor a flow of between about 0.02 and 50 μl/day, usually 0.2 to 10 μl/dayand often 0.2 to 2.0 μl/day. Additionally, a catheter or other systemmay be attached to the end of the flow modulator delivery orifice 30 toprovide for delivery of the beneficial agent formulation at a siteremoved from the implantable osmotic delivery system. Such systems areknown in the art and are described, for example, in U. S. Pat. Nos.3,732,865 and 4,340,054, the disclosures of which are incorporatedherein by reference.

Although preferred, the delivery path 32 need not be formed in theexterior surface of the flow modulator body 21. The flow modulator body21 need not have the delivery path 32. For example, the interior surface43 of the cylindrical enclosure 42 may include threads of apredetermined pitch, amplitude, and cross-sectional area. Such threadsformed within the interior surface 43 of the enclosure 42 may functionas the delivery path 32 for the beneficial agent 44. In such anembodiment, the flow modulator body 21 may have a smooth cylindricalouter surface which seals the second opening 39 in the enclosure 42,except for the delivery path 32 formed in the interior surface 43 of theenclosure. In such an embodiment, the flow modulator assembly 20 willcontinue to modulate flow because the outer surface continues to definethe cross-sectional area of the delivery path 32. Alternatively, theinterior surface 43 of the enclosure 42 and the outer cylindricalsurface of the flow modulator body 21 each may have female threads, malethreads, or any combination thereof to form a delivery path 32 ofpredetermined size. Furthermore, the delivery path 32 need not be asingle helically shaped channel, it may be a straight or curved channelor series of channels.

As illustrated in FIG. 3, the exemplary osmotic delivery system flowmodulator assembly 20 includes a first hole or vent hole 24 and asecond, additional hole or fill hole 22. The vent hole 24 and the fillhole 22 are elongated, straight, and run longitudinally and parallelthrough the body 21 of the osmotic delivery system flow modulatorassembly 20. In other words, the longitudinal axis of the fill hole 22and the longitudinal axis of the vent hole 24 are substantiallyperpendicular to at least one of the opposing ends 37, 38 of the flowmodulator. Because the flow modulator body 21 is preferably cylindricalsuch that it is constructed and arranged for at least partialpositioning in the second opening 39 of the cylindrical enclosure 42,the vent hole 24 and fill hole 22 are parallel with the interior surface43 and cylindrical outer surface of the enclosure 42.

The vent hole 24 and the fill hole 22 run or extend completely throughthe body of the flow modulator, and communicate the first opposing end37 with the second opposing end 38 of the cylindrical flow modulatorbody 21. As illustrated in FIG. 2, the vent hole 24 and the fill hole 22each have a circular cross-sectional shape of the same diameter.Although the cross-sectional shape of the vent hole 24 and the fill hole22 is preferably circular, other shapes for the holes are contemplated.For example, square, triangular, or oval cross-sectional shaped holes22, 24 would all be within the confines of the present invention.Furthermore, the longitudinal axis of the holes 22, 24 need not beparallel with the longitudinal axis of the flow modulator body 21. Forexample, the holes 22, 24 may be located at an angle with respect to thelongitudinal axis of the modulator body 21, or spiral through the flowmodulator body 21.

The flow modulator assembly 20 is best described in reference to theosmotic delivery system 40 according to another embodiment of thepresent invention.

FIG. 4 illustrates an example of an osmotic delivery system 40 accordingto the present invention. The configuration illustrated in FIG. 4 is oneexample of an osmotic delivery device and is not to be construed aslimiting the present invention. The present invention is generallyapplicable to all osmotic delivery devices having any number of shapes,and to all such devices administered in any variety of methods such asoral, ruminal, and implantable osmotic delivery techniques.

The osmotic drug delivery system 40, as illustrated in FIG. 4, includesan elongated substantially cylindrical enclosure 42 having a secondopening 39 for receiving the osmotic delivery system flow modulator 20,and a first opening 45 located opposite the flow modulator opening orsecond opening 39 for receiving the semipermeable plug 48. The deliveryorifice 30 of the osmotic delivery system flow modulator assembly 20 isfor delivering the beneficial agent 44 from the osmotic delivery system40.

The elongated and cylindrical enclosure 42 is formed of a material whichis sufficiently rigid to withstand expansion of the osmotic agent 47without changing size or shape. The elongated enclosure 42 is preferablysubstantially impermeable to fluids in the environment of use as well asto ingredients contained within the delivery system 40 such that themigration of such materials into or out of the system through theimpermeable material is so low as to have substantially no adverseimpact on the function of the osmotic delivery system.

Materials which may be used for the enclosure 42 must be sufficientlystrong to ensure that the enclosure will not leak, crack, break, ordistort under stresses to which it would be subjected duringimplantation or under stresses due to the pressures generated duringoperation. The enclosure 42 may be formed of chemically inert andbiocompatible, natural or synthetic materials which are known in theart. The enclosure material is preferably a non-bioerodible materialwhich remains in the patient after use, such as titanium. However, thematerial of the enclosure may alternatively be a bioerodible materialwhich bioerodes in the environment after dispensing of the beneficialagent. Generally, preferred materials for the enclosure 42 are thoseacceptable for human implantation.

In general, typical materials of construction suitable for the enclosure42 according to the present invention include non-reactive polymers orbiocompatible metals or alloys. The polymers include acrylonitrilepolymers such as acrylonitrile-butadiene-styrene terpolymer, and thelike; halogenated polymers such as polytetraflouroethylene,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and thelike. Metallic materials useful for the enclosure 42 include stainlesssteel, titanium, platinum, tantalum, gold, and their alloys, as well asgold-plated ferrous alloys, platinum-plated ferrous alloys,cobalt-chromium alloys and titanium nitride coated stainless steel.

An enclosure 42 made from the titanium or a titanium alloy havinggreater than 60%, often greater than 85% titanium is particularlypreferred for the most size-critical applications, for high payloadcapability and for long duration applications, and for thoseapplications where the formulation is sensitive to body chemistry at theimplantation site or where the body is sensitive to the formulation. Incertain embodiments, and for applications other than the fluid-imbibingdevices specifically described, where unstable beneficial agentformulations are in the enclosure 42, particularly protein and/orpeptide formulations, the metallic components to which the formulationis exposed must be formed of titanium or its alloys as described above.Within the enclosure 42 is a beneficial agent 44 to be delivered. Such abeneficial agent 44 may optionally include pharmaceutically acceptablecarriers and/or additional ingredients such as anti-oxidants,stabilizing agents, permeation enhancers, etc.

The present invention applies to the administration of beneficial agents44 in general, which include any physiologically or pharmacologicallyactive substance. The beneficial agent 44 in the osmotic delivery system40 may be any of the agents which are known to be delivered to the bodyof a human or an animal such as medicaments, vitamins, nutrients, or thelike. The beneficial agent 44 may also be an agent which is delivered toother types of aqueous environments such as pools, tanks, reservoirs,and the like. Included among the types of agents which meet thisdescription are biocides, sterilization agents, nutrients, vitamins,food supplements, sex sterilants, fertility inhibitors and fertilitypromoters.

Drug agents which may be delivered by the present invention includedrugs which act on the peripheral nerves, adrenergic receptors,cholinergic receptors, the skeletal muscles, the cardiovascular system,smooth muscles, the blood circulatory system, synoptic sites,neuroeffector junctional sites, endocrine and hormone systems, theimmunological system, the reproductive system, the skeletal system,autacoid systems, the alimentary and excretory systems, the histaminesystem and the central nervous system. Suitable agents may be selectedfrom, for example, proteins, enzymes, hormones, polynucleotides,nucleoproteins, polysaccharides, glycoproteins, lipoproteins,polypeptides, steroids, analgesics, local anesthetics, antibioticagents, anti-inflammatory corticosteroids, ocular drugs and syntheticanalogs of these species.

Examples of drugs which may be delivered by devices according to thisinvention include, but are not limited to prochlorperzine edisylate,ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride,procainamide hydrochloride, amphetamine sulfate, methamphetaminehydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate,phenmetrazine hydrochloride, bethanechol chloride, methacholinechloride, pilocarpine hydrochloride, atropine sulfate, scopolaminebromide, isopropamide iodide, tridihexethyl chloride, phenforminhydrochloride, methylphenidate hydrochloride, theophylline cholinate,cephalexin hydrochloride, diphenidol, meclizine hydrochloride,prochlorperazine maleate, phenoxybenzamine, thiethylperzine maleate,anisindone, diphenadione erythrityl tetranitrate, digoxin,isoflurophate, acetazolamide, methazolamide, bendroflumethiazide,chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol,allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol,ethinyl estradiol 3-methyl ether, prednisolone, 17∝-hydroxyprogesteroneacetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, aspirin,indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, colchicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hormone, follicle stimulating hormone,chorionic gonadotropin, gonadotropin releasing hormone, bovinesomatotropin, porcine somatotropin, oxytocin, vasopressin, GRF,prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone,LHRH, LHRH agonists and antagonists, leuprolide, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, coagulationfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

The beneficial agent 44 can be present in this invention in a widevariety of chemical and physical forms, such as solids, liquids andslurries. On the molecular level, the various forms may includeuncharged molecules, molecular complexes, and pharmaceuticallyacceptable acid addition and base addition salts such as hydrochlorides,hydrobromides, sulfate, laurylate, oleate, and salicylate. For acidiccompounds, salts of metals, amines or organic cations may be used.Derivatives such as esters, ethers and amides can also be used. Abeneficial agent 44 can be used alone or mixed with other beneficialagents.

The enclosure 42 receives the osmotic agent 47, which in the embodimentof the present invention depicted in FIG. 4 is two osmotic tablets.Osmotic agents 47, specifically the osmotic tablets illustrated in FIG.4, drive the osmotic flow of the osmotic delivery system 40. However,the osmotic agent 47 need not be a tablet; it may be other conceivableshapes, textures, densities, and consistencies and still be within theconfines of the present invention. For example, the osmotic agent 47 maybe in the form of a powder. The osmotic tablet is preferably andinitially non-flowable and solid, but upon insertion of the osmoticdelivery system 40 into the environment of use, an external liquidpermeates through the semipermeable plug 48, causing the osmotic tabletsto assume a flowable form.

The embodiment of the present invention illustrated in FIG. 4 includes adividing member 46, which may be movable or stationary within theenclosure 42. The osmotic agent 47 within the enclosure 42 is separatedfrom the beneficial agent 44 by the dividing member 46. The dividingmember 46 may be in the form of a slidable or movable partition or astationary and stretchable partition member. The dividing member 46 ispreferably movable and is formed from an impermeable resilient materialthat includes annular ring shape protrusions which form a seal with theinner surface 43 of the enclosure 42.

The dividing member 46 is a substantially cylindrical member which isconfigured to fit within the enclosure 42 in a sealing manner which alsoallows the dividing member to slide along the longitudinal direction ofthe enclosure. The dividing member 46 isolates the beneficial agent 44from the environmental liquids that are permitted to enter enclosure 42through the semipermeable plug 48 such that in use, at steady-stateflow, the beneficial agent is expelled through the delivery orifice 30at a rate corresponding to the rate at which liquid from the environmentof use flows into the osmotic agent 47 through the semipermeable plug.As a result, the flow modulator assembly 20 and the beneficial agent 44will be protected from damage and their functionality will not becompromised even if the enclosure 42 adjacent the osmotic agent becomesdeformed.

The dividing member 46 is preferably made of a material that is of lowerhardness than the enclosure 42 and will deform to fit the lumen of theenclosure to provide a fluid tight compression seal with the enclosure.The materials from which the dividing member 46 may be made arepreferably elastomeric materials that are impermeable and include butare not limited to polypropylene, rubbers such as EPDM, silicone rubber,butyl rubber, and the like, and thermoplastic elastomers such asplasticized polyvinylchloride, polyurethanes, Santoprene®, C-flex TPE(Consolidated Polymer Technologies, Inc.), and the like. The dividingmember 46 may be a self-loading or a compression-loaded design. Othermaterials suitable for the dividing member 46 are elastomeric materialsincluding the non-reactive polymers listed above, as well as elastomersin general, such as polyurethanes and polyamides, chlorinated rubbers,styrene-butadiene rubbers, and chloroprine rubbers.

However, the present invention need not include the dividing member 46.In such an embodiment, the beneficial agent 44 and the osmotic agent 47may be separated by an interface between the osmotic agent and thebeneficial agent or the may together form a homogeneous mixture.

As illustrated in FIG. 4, the osmotic delivery system 40 includes thesemipermeable membrane plug 48 which is inserted into the first opening45 within the enclosure 42. The semipermeable membrane plug 48 allowsliquid to pass from an environment of use into the enclosure 42 to causethe osmotic agent 47 to swell. The semipermeable material forming theplug 48 is largely impermeable to materials within the enclosure 42 andother ingredients within the environment of use. Materials from whichthe semipermeable membrane plug 48 may be fabricated are well knownwithin the art. The semipermeable membrane plug 48 is of a lowerhardness material and will conform to the shape of the enclosure 42 toproduce a liquid-tight seal with the interior of the enclosure 42 uponwetting. Materials from which the semipermeable membrane plug 48 aremade are those that are semipermeable, can conform to the shape of theenclosure 42 upon wetting, and adhere to the rigid interior surface 43of the enclosure.

The polymeric materials from which the semipermeable plug 48 may be madevary based on the pumping rates and system configuration requirements,and include, but are not limited to, plasticized cellulosic materials,enhanced polymethylmethacrylates such as hydroxyethylmethacrylate(HEMA), and elastomeric materials such as polyurethanes and polyamides,polyether-polyamide copolymers, thermoplastic copolyesters, and thelike.

The osmotic tablets are osmotic agents 47 which are liquid attractingagents used to drive the flow of the beneficial agent 44. The osmoticagent 47 may be an osmagent, an osmopolymer, or a mixture of the two.Species which fall within the category of osmagent, i.e., thenon-volatile species which are soluble in water and create the osmoticradiant driving the osmotic inflow of water, vary widely. Examples arewell known in the art and include magnesium sulfate, magnesium chloride,potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate,sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol,urea, magnesium succinate, tartaric acid, raffinose, and variousmonosaccharides, oligosaccharides and polysaccharides such as sucrose,glucose, lactose, fructose, and dextran, as well as mixtures of any ofthese various species.

Species which fall within the category of osmopolymer are hydrophilicpolymers that swell upon contact with water, and these vary widely aswell. Osmopolymers may be of plant or animal origin, or synthetic, andexamples of osmopolymers are well known in the art. Examples include:poly(hydroxy-alkyl methacrylates) with molecular weight of 30,000 to5,000,000, poly(vinylpyrrolidone) with molecular weight of 10,000 to360,000, anionic and cationic hydrogels, polyelectrolyte complexes,poly(vinyl alcohol) having low acetate residual, optionally cross-linkedwith glyoxal, formaldehyde or glutaraldehyde and having a degree ofpolymerization of 200 to 30,000, a mixture of methyl cellulose,cross-linked agar and carboxymethylcellulose, a mixture of hydroxyproplmethycellulose and sodium carboxymethylcellulose, polymers ofN-vinyllactams, polyoxyethylene-polyoxypropylene gels,polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyurea gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross-linkedindene-maleic anhydride polymers, Good-Rite polyacrylic acids havingmolecular weights of 80,000 to 200,000, Polyox Polyethylene oxidepolymers having molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps acrylate polymer polysaccharides.

In assembling the osmotic delivery device 40 according to one embodimentof the present invention, the movable dividing member 46 is firstinserted into the first opening 45 of the enclosure 42. The osmoticagent 47 is then positioned or placed through the same first opening 43such that it is adjacent to the movable dividing member 46. Thereafter,the semipermeable plug 48 is inserted into the same first opening 43,effectively sealing this opening. Thus, the osmotic agent 47 is adjacentto the semipermeable plug 48 and, preferably, in fluid communicationwith the semipermeable plug 48 such that fluids may flow through thesemipermeable portion to the osmotic agent. The osmotic delivery system40 is then preferably rotated such that the second opening 39 of theenclosure 42 located opposite the semipermeable plug 48 faces verticallyupward.

In previous osmotic delivery systems, the beneficial agent is nextmeasured and inserted into an opening of the system such that it islocated above the dividing member. Ordinarily, the last step inassembling these systems is to insert a delivery plug into the thisopening. However, the osmotic delivery system 40 according to oneembodiment of the present invention includes the osmotic delivery systemflow modulator assembly 20 illustrated in FIG. 4. The beneficial agent44 may be delivered to the interior of the enclosure through the fillhole 22 in the flow modulator body 21.

Thus, when assembling the osmotic delivery system 40 according to thepresent invention, the flow modulator body 21 is first inserted at leastpartially into the second opening 39 of the enclosure 42 opposite thesemipermeable plug 48 before the beneficial agent 44 is delivered intothe system. The flow modulator body 21 is preferably inserted into theenclosure 42 such that the head surface 34 abuts against the enclosure42. Thus, the head surface 34 controls the depth that the flow modulatormay be inserted into the second opening 41 in the enclosure 42. The headsurface 34 preferably extends perpendicularly from the longitudinal axisof the flow modulator body 21 such that it extends radially away fromthe threads 36. The delivery path 32, in the embodiment of the flowmodulator assembly 20 depicted in FIG. 1, ends at the delivery orifice30, which is located on or near the head surface 34.

Thereafter, a pipette, syringe, or other similar device, preferablyfilled with the beneficial agent 44, is arranged above or within thefill hole 22, and the beneficial agent is released into the fill hole ata predetermined rate, delivering the beneficial agent into the interiorof the enclosure 42 through the fill hole. The fill hole 22 may be sizedto matingly receive a fill tube of a syringe, or may also be larger thanthe diameter of the fill tube of the syringe such that the fill holealso permits venting like the vent hole 24. The predetermined rate ofrelease of beneficial agent 44 from the pipette is such that a gas, suchas air, within the beneficial agent or the enclosure 42 has theopportunity to escape through the vent hole 24 as the incomingbeneficial agent is delivered through the fill hole 22 and fills theinterior of the enclosure. Thus, it is apparent that the vent hole 24,and all of its possible configurations discussed above, acts as meansfor venting the osmotic delivery system 40 when the beneficial agent 44is inserted into the osmotic delivery system. The beneficial agent 44 isdelivered for a predetermined period of time such that the beneficialagent fills the enclosure 42, and at least partially fills the fill hole22 and the vent hole 24. Finally, the caps 26, illustrated in FIG. 3 areinserted into the vent hole 24 and fill hole 22, capping or sealing theholes such that beneficial agent 44 located within the delivery system40 will not escape from the enclosure 42, save from the delivery orifice30.

The caps 26, or means for sealing the holes 22, 24 from the surroundingenvironment, may be fashioned from a material similar to that of theosmotic delivery system flow modulator body 21, and should sufficientlyseal the fill hole 22 and vent hole 24 from the environment of use suchthat external liquids from the environment of use do not substantiallyleak or diffuse into the osmotic delivery system 40, and such thatpressures generated from the osmotic agent 47 within the osmoticdelivery system 40 do not substantially cause the beneficial agent 44 toleak out from the fill hole 22 or vent hole 24. The caps 26 may pressfit or thread into the holes 22, 24. However, the fill hole 22 and venthole 24 need not be sealed by the caps 26. Plugs, inserts, moltenplastics, rods, and other devices or items may also be used to cap thefill hole 22 and the vent hole 24 such that they also function as meansfor sealing. Likewise, one cap may be used to cover and seal both holes22, 24.

The fill hole 22 and the vent hole 24 are sized to accommodate thepredetermined rate that beneficial agent 44 is delivered into the fillhole. If this delivery rate is relatively slow, the fill hole 22 mayhave a smaller diameter and/or a longer length. If the predeterminedrate of delivery of beneficial agent 44 into the fill hole 22 isrelatively fast, the fill hole 22 must have a larger diameter and/or ashorter length such that the beneficial agent does not overflow the fillhole 22 as it is delivered through the hole. The fill hole 22 may havesufficient volume to accommodate the rate of beneficial agent 44delivered through the fill hole such that there is relatively littlepressure drop across the fill hole during delivery of the beneficialagent through the fill hole.

Alternatively, the beneficial agent 44 may be forced into and throughthe fill hole 22 such that there is a significant pressure drop acrossthe fill hole, which also forces air quickly out of the enclosure 42through the vent hole 24.

The preferred size of the fill hole 22 is also dependent upon the sizeof the vent hole 24. Because the flow modulator forms a seal with theinterior surface of the enclosure, the vent hole 24 should besufficiently large to accommodate the rate of escaping air or gas fromwithin the enclosure 42, which roughly equals the rate that beneficialagent 44 is pipetted into the fill hole 22, depending upon the amount ofgas allowed to escape through the fill hole 22. Because air iscompressible, the vent hole 24 may be smaller than the fill hole, yetaccommodate the same rate of escaping air as entering beneficial agent44. However, once the enclosure 42 is sufficiently full of beneficialagent 44 such that the agent begins to rise into the fill hole 22 andvent hole 24, the rate that the beneficial agent rises in the vent holepreferably matches that of the rising rate in the fill hole. Thus, thefill hole 22 and vent hole 24 preferably have the same volume, which inthe embodiment of the present invention illustrated in FIG. 3, isobtained by matching the diameters and lengths of the cylindrical filland vent holes.

However, if the flow moderator body 21 is made from a resilientmaterial, the fill hole 22 and vent hole 24 must not be overly largesuch that the sealing capacity of the threads 36 against the interiorsurface 43 is compromised.

As shown in FIGS. 3 and 4, the fill hole 22 and the vent hole 24 arepreferably located separate from the delivery path 32 such that theholes and the path are not integral. This is preferred because, althoughsome venting may occur in the delivery path 32, it is typically toosmall to effectively vent the osmotic delivery system 40 without theassistance of a vacuum during the beneficial agent filling process.

Assembling the osmotic delivery system 40 in the above described manneris advantageous because the amount of wasted beneficial agent 44 isreduced. Beneficial agent 44 is preferably delivered into the enclosure42 through the fill hole 22 until the fill hole and the vent hole 24 areboth substantially filled with beneficial agent. Thereafter, the fillhole 22 and the vent hole 24 are capped with the caps 26. When the holes22, 24 are capped with the caps 26, a minute amount of surplusbeneficial agent 44 is expelled from the flow modulator. This reducedamount of beneficial agent expelled when assembling an osmotic deliverysystem 40, as compared to past assembly methods, reduces the costs ofassembly. Because the amount of expelled and wasted beneficial agent isreduced, it is also easier to determine the precise amount of beneficialagent 44 remaining in the osmotic delivery system.

As described above, when delivering the beneficial agent 44 into theosmotic delivery system 40, the vent hole 24 permits gas within theenclosure of the osmotic delivery system to escape from the system.Thus, when the osmotic delivery system 40 is completely assembled, theamount of gas within the system is reduced. This reduction of trappedair or gas within the system 40 is advantageous because the time tostart-up of delivery of beneficial agent 44 from the delivery system tothe environment of use is reduced.

When the osmotic delivery system 40 is eventually placed into anenvironment of use, the osmotic agent 47 imbibes fluid through thesemipermeable plug 48 and expands, creating osmotic pressure within theenclosure 42. This osmotic pressure forces the beneficial agent 44through the delivery path 32. Because the amount of gas or air withinthe enclosure 42 is reduced during assembly of the osmotic deliverysystem 40, the osmotic agent 47 need not first compress air within thebeneficial agent or interior of the delivery system before forcing thebeneficial agent into the delivery entrance 28. Hence, the start-upperiod to delivery of the beneficial agent 44 is not delayed by theamount of time which would ordinarily be required to compress airpockets within the osmotic delivery system 40. Furthermore, the chancethat significant amounts of air or gas may expel from the system,causing possible health risks, is reduced.

FIGS. 5-8 illustrate osmotic delivery system flow modulator assemblies120, 220 according to further embodiments of the present invention. Theosmotic delivery system flow modulator assemblies 120, 220 will bedescribed in reference to exemplary osmotic delivery systems 140, 240according to further embodiments of the present invention illustrated inFIGS. 7 and 8. Each of the osmotic delivery systems 140, 240 includesthe respective flow modulator assemblies 120, 220. Features on the flowmodulator assemblies 120, 220, and osmotic delivery systems 140, 240that are similar to features on the flow modulator assembly 20 andosmotic delivery system 40 are assigned corresponding reference numbers,increased by 100's. Thus, the above description of the benefits andfunctions of the different components of the flow modulator assembly 20,osmotic delivery system 40, and methods of assembling associatedtherewith also apply to the flow modulator assemblies 120, 220 andosmotic delivery systems 140, 240. However, the flow modulatorassemblies 120, 220 and the osmotic delivery systems 140, 240 includeadditional features and inherent functions, as described below.

As shown in FIGS. 5 and 6, the osmotic delivery system flow modulatorassembly 120 includes a flow modulator body 121 having a filling andventing hole 124 located through the body of the flow modulator andcommunicating the opposing ends 137, 138 of the body. The osmoticdelivery system flow modulator assembly 120, similar to the osmoticdelivery system flow modulator assembly 20, lessens the chance that airor gas pockets will form in the enclosure 142 of the osmotic deliverysystem 140 during assembly of the system, specifically during thedelivery of the beneficial agent 144 into the enclosure of the systemthrough the hole 124 in the flow modulator body 121. Because use of theosmotic delivery system flow modulator assembly 120 with the osmoticdelivery system 140 lessens the chance of air or gas formations withinthe enclosure 142, the time to start up of delivery of the beneficialagent 144 and performance of the system is enhanced. Use of the flowmodulator assembly 120 also lessens the chance that beneficial agentwill be wasted during assembly of osmotic delivery system 140, and alsoreduces back diffusion of substances from the external environment intothe osmotic delivery system.

FIGS. 5 and 6 illustrate an exemplary osmotic delivery system flowmodulator assembly 120 according to one embodiment of the presentinvention. Like the osmotic delivery system flow modulator assembly 20depicted in FIG. 1, the body 121 of the flow modulator assembly 120 isconstructed and arranged for at least partial positioning in the osmoticdelivery system enclosure 142. The osmotic delivery system flowmodulator assembly 120 may also be made from the materials from whichthe osmotic delivery system flow modulator 20 assembly may be made.Likewise, the delivery path 132 of the osmotic delivery system flowmodulator assembly 120 may also be configured like the delivery path 32of the flow modulator assembly 20. Thus, it is apparent that the flowmodulator 120 is similar in many aspects to the flow modulator 20.However, the flow modulator body 121 of the flow modulator assembly 120,as shown in FIGS. 5 and 6, only includes one hole 124 which communicatesthe opposing ends 137, 138 of the flow modulator body 121. As describedbelow, the hole 124 may function as both a fill hole and a vent hole.

In assembling the osmotic delivery system 140, the movable dividingmember 146 is first inserted into a first opening of the enclosure 142.The osmotic agent 147 is then positioned or placed through the samefirst opening such that is adjacent to the movable dividing member 146.Thereafter, the semipermeable plug 148 is inserted into the same firstopening, effectively sealing this opening. The osmotic delivery system140 is then preferably rotated such that the second opening of theenclosure 142 located opposite from the semipermeable plug 148 facesvertically upward.

At this point, the beneficial agent 144 may be delivered to the interiorof the enclosure 144 through the hole 124 in the flow modulator body121. Thus, when assembling the osmotic delivery system 140 according tothe present invention, the flow modulator body 121 may be inserted atleast partially into the second opening of the enclosure 142 oppositethe semipermeable plug before the beneficial agent 144 is delivered intothe system. The flow modulator body 121 is preferably inserted in theenclosure 142 such that both ends 137, 138 of the flow modulator bodyare within the interior of the enclosure 142.

Thereafter, a pipette, syringe, or other similar filling device,preferably filled with the same beneficial agent 144, is arranged abovethe hole 124 and the beneficial agent is released into the hole at apredetermined rate, delivering the beneficial agent into the interior ofthe enclosure 142 through the hole 124. The predetermined rate ofrelease of beneficial agent 144 from the pipette is such that air or gaswithin the beneficial agent and the enclosure 142 has the opportunity toescape through the hole 124 as incoming beneficial agent is deliveredthrough the hole 124 and fills the interior of the enclosure 142. Thus,it is apparent that the hole 124, and all of its possible configurationssuch as that discussed above in regard to the holes 22, 24 acts as meansfor venting the osmotic delivery system 140 when the beneficial agent144 is inserted into the osmotic delivery system. Hence, the hole 124functions as both a fill hole and a vent hole. The beneficial agent 144is delivered for a predetermined period of time such that the beneficialagent fills the enclosure 142 and the hole 124 of the flow modulatorbody 121.

Alternatively, a portion of the beneficial agent 144 may be firstdelivered into the enclosure 142, and then the flow modulator body 121may be at least partially inserted into the second opening of theenclosure such that the remainder of the beneficial agent may bedelivered into the enclosure through the hole 124.

After the beneficial agent has been delivered into the enclosure 142,the stopper 170 illustrated in FIGS. 5-7 is inserted into the hole 124.As illustrated in FIG. 6, the stopper 170 is a pin-like member having atip 173 and a head 175 located opposite from one another. The stopper170 also includes a shaft 171 located between the tip 173 and the head175. The shaft 171 is configured and sized to fit in the hole 124 of theflow modulator 120 such that a seal is formed between the exteriorsurface 179 of the shaft 171 and the interior surface of the hole 124.Thus, the stopper 170 functions similar to the caps 26 depicted in FIG.3. As such, the stopper 170 may be fashioned from a material similar tothat of the osmotic delivery system flow modulator 120, and shouldsufficiently seal the hole 124 from the environment of use such thatexternal liquids from the environment of use do not leak into theosmotic delivery system, and such that pressures generated from theosmotic agent 147 within the osmotic delivery system 140 do not causethe beneficial agent 144 to leak out from the hole 124. Thus, thestopper 170 may press fit, thread into the hole 124, and/or be fixedlyadhered within the hole with the assistance of an adhesive. However, thestopper 170 need not be a pin-shaped member. A plug, cork, peg, pin,insert, molten plastic, rod, check valve, lid, top, cap or other deviceor item(s) may be used to stop or close the hole 124 such that the holeis sealed. However, as described below, the stopper 170 is preferablyshaped as described below such that it attaches or secures a partition160 to the flow modulator body 121.

The stopper 170 may be made from any chemically inert and biocompatible,natural, or synthetic material which is known in the art. The stoppermaterial is preferably a non-bioerodible material which remains in thepatient after use, such as titanium. The preferred titanium for thestopper 170 is similar or equal to that from which the enclosure 142 maybe made from. However, the material of the stopper 170 may alternativelybe a bioerodible material which bioerodes in the environment after theosmotic delivery system has dispensed the beneficial agent 144.Generally, preferred materials for the stopper 170 are those acceptablefor human implantation. Furthermore, the exterior surface 179 of theshaft 171 may be coated with a material which will help form a sealbetween the exterior surface 179 and the interior surface of the hole124, such as a gold plating.

As shown in FIGS. 5 and 6, the shaft 171 of the stopper 170 iscylindrical and elongated and sized to matingly fit within the hole 124of the flow modulator body 121. Located opposite from the tip 173 andadjacent to the head 175 is a tapered section 176 which has a smallerdiameter than that of the shaft 171. After the exterior surface 179 ofthe shaft 171 tapers to the smaller diameter of the tapered section 176,it curvingly angles at approximately 45° from the tapered section toform the arcuate surface 177 and to define the head 175 of the stopper170. The arcuate surface 177 of the stopper 170 ends at a diameter whichis larger than that of the shaft 171 and the tapered section 176.

After the beneficial agent 144 has been inserted into the enclosure 142through the hole 124 in the flow modulator 120, the stopper 170 isinserted into the hole 124 to seal the hole in the manner describedabove. However, before the stopper 170 is inserted into the hole 124,the stopper is fitted with the partition 160 illustrated in FIGS. 5 and6.

In the embodiment illustrated in FIGS. 5-7, the partition 160 is adisc-shaped member having a predetermined thickness and smooth exteriorsurface 161. The partition 160 is preferably made from an elastomericmaterial, which may be similar or equal to that of the flow modulatorbody 121. Two preferred materials for the partition 160 are silicone andC-Flex, manufactured by Consolidated Polymer Technologies.

The above-described preferred materials for the partition 160 aresufficiently soft and flexible such that the tip 173 of the stopper 170may pierce through the thickness of the partition 160 and such that thepartition 160 flexes as the shaft 171 is forced through a pierced slit,cut, or rip created with the tip 173. Thus, the partition 160illustrated in FIG. 6 preferably does not include a performed hole forreceiving the stopper 170, such that the tip 173 of the stopper 170 mustbe forcibly pierced through the partition 160 so that the partition 160is slidable up the shaft 171 of the stopper.

After the partition 160 has been pierced by the tip 173, the partition160 is slid along the shaft 171 until it reaches the tapered section 176of the stopper 170. Because the tapered section 176 of the stopper 170is a smaller diameter than that if the shaft 171, it is adapted toreceive the partition 160 such that the partition is attached to thestopper 170 and will not easily slide down the shaft 171 toward the tip173. However, the stopper 170 need not include the tapered section 176.Although the material for the partition 160 is sufficiently elastomericto allow the partition to slide along the shaft 171 after it is piercedby the tip 173, it is also sufficiently rigid such that it will noteasily slide beyond the head 175 which has a greater diameter than thatof the shaft 171 and tapered section 176. That is, the head 175 isconfigured to prevent the partition 160 from being removed from the headend of the stopper 170, as shown in FIG. 7. The head 175 may also beother configurations such as the top of a “T”, a retaining ring, nut,bolt, item fastened to the shaft 176, or other device which prevents thepartition 160 from being removed from the head end of the shaft 171.Thus, after the partition 160 has been fitted on the shaft 171 and thestopper 170 has been inserted into the hole 124, the partition issecured to the flow modulator body 121, between the flow modulator bodyand the head 175 of the stopper.

Although the partition 160 depicted in FIGS. 5-7 is formed from a solidand integral piece, it need not be so configured. The partition 160 mayalso include an opening, slit, cut, or a hole for receiving the stoppershaft 171. Thus, with such an embodiment, the tip 173 of the stopper 170need not be sharp or pin-like to pierce the partition 160. Likewise, thepartition 160 may have an indentation located at or near the center ofthe partition 160 to define a predetermined location where the tip 173of the stopper 170 should pierce the partition upon application of forceto the stopper.

FIG. 7 illustrates the flow modulator assembly 120 positioned in anopening of the osmotic delivery system 140. Once the partition 160 hasbeen positioned on the tapered section 176 of the stopper 170, and theflow modulator body 121 has been press-fit into the opening of theenclosure 142, the top 178 of the head 175 of the stopper 170 may bepressed into the hole 124 such that the stopper 170 and partition 160attached thereto are received by the opening in the enclosure 142. Thestopper 170 is preferably inserted into the hole 124 until the partition160 abuts against a surface of the enclosure 142. In this manner, thepartition 161 and the surface of the enclosure 142 define a one-way sealor check valve 141 which substantially prevents liquids external of theosmotic delivery system from the entering the interior of the enclosure142, but which also permits the beneficial agent 144 within theenclosure 142 to exit the osmotic delivery system 140. Once the stopper170 has been inserted into the hole 124, it is apparent that the osmoticdelivery system flow modulator assembly 120 is at least partially withinthe interior of the enclosure 142.

As shown in FIG. 7, the partition 160 abuts against the interior surface143 of the enclosure 142 to define the check valve 141 between theexterior surface 161 of the partition 160 and the interior surface 143.Thus, when the osmotic delivery system 140 is eventually placed into anenvironment of use, the osmotic agent 147 imbibes fluid through thesemipermeable plug 148 and expands, creating osmotic pressure within theenclosure 142. This osmotic pressure forces the beneficial agent 144through the delivery path 132 and eventually through the check valve 141between the exterior surface of the partition 161 and the interiorsurface 143 of the enclosure 142.

As shown in FIG. 7, the stopper 170 and the partition 160 attachedthereto are at least partially inserted into the enclosure 142 of theosmotic delivery system 140. In the embodiment shown in FIG. 7, the flowmodulator assembly 120 is fully inserted within the enclosure 142 suchthat the partition 160 is also fully within the enclosure 142. Thus, asdescribed above, the partition surface 161 abuts against the interiorsurface 143 of the enclosure 142 to define the check valve 141. Becausethe check valve 141 is formed between the exterior surface 161 of thepartition 160 and the interior surface 143 of the enclosure 142, it isnecessary that the partition 160 be sufficiently large such that it willabut against the interior surface 143 when the flow modulator assembly120 is inserted into the opening of the delivery system 140. Thus, inthe embodiment of the flow modulator assembly 120 depicted in FIGS. 5-7,the partition 160 has a greater diameter than that of the flow modulatorbody 121 to assure that the outer surface 161 of the partition 160 willabut against the interior surface 143 of the enclosure 142 when the flowmodulator 120 is inserted into the enclosure.

The diameter, thickness, and material of the partition 160 control theamount of pressure required to “open” the check valve 141 so as to allowthe beneficial agent 144 to flow past or through the check valve afterit has travelled through the delivery channel 132.

For example, the diameter or thickness of the partition 160 may beincreased such that the amount of pressure required to “open” the checkvalve 141 is increased. The size of the head 175 of the stopper 170 mayalso be varied and/or have differently shaped surfaces so as to controlthe “opening” check valve pressure. Furthermore, the delivery path 132may be located elsewhere in the flow modulator assembly 120. Forinstance, a portion of the delivery path 132 may also be defined by thecheck valve 141 of the partition 160.

FIG. 8 depicts another embodiment of an osmotic delivery system 240which includes another embodiment of a flow modulator assembly 220. Theflow modulator assembly 220 is similar to the flow modulator assembly120, and the above description of the benefits and function of thedifferent components of the flow modulator assembly 120 also applies tothe flow modulator assembly 220. Thus, features on the flow modulatorassembly 220 that are similar to features on the flow modulator assembly120 are assigned corresponding reference numbers, increased by 100.However, the stopper 270 and the partition 260 are shaped differentlythan that of the stopper 170 and partition 160 depicted in FIGS. 5-7.The stopper 270 and the partition 260 have larger dimensions than thestopper 170 and partition 160 such that the amount of osmotic pressurerequired to “open” the check valve 241 so as to allow the beneficialagent 144 to flow past or through the check valve is increased.

More specifically, the diameter and thickness of the partition 260 isgreater than that of the partition 160. Because of these increaseddimensions, the exterior surface 261 of the partition 260 abuts againstthe exterior surface of the osmotic delivery system enclosure 242 todefine the check valve 241. Contrary to the check valve 141 shown inFIG. 7, the check valve 241 illustrated in FIG. 8 is formed between theexterior surface of the enclosure 242 of the osmotic delivery system240. Thus, in this embodiment of the present invention, the head 275 ofthe stopper 270 and the partition 260 are not completely within theinterior of the enclosure 242, but are only partially located thereinsuch that at least a portion of the exterior surface of the partition260 abuts against the exterior surface of the enclosure 242. However,the partition 260 may be a greater diameter such that the head 275 maybe located completely within the enclosure 242 and the exterior surfaceof the partition may still abut against an exterior surface of theenclosure. In an alternative embodiment, not shown, the partition 160,260 does not form a check valve. That is, the partition 160, 260 neednot abut against a surface of the enclosure 142, 242, but may assist insealing the hole 124, 224.

Additionally, the partition 160, 260 need not be included in the osmoticdelivery system 140, 240. That is, the stopper 170, 270 can be insertedinto the cylindrical hole or channel 124, 224 without the partition 160,260 attached thereto. An osmotic delivery system having such a flowmodulator assembly (without a partition) would thus not include a checkvalve ordinarily formed by the partition. However, the delivery path ofsuch a flow modulator assembly, as described above, can be sized suchthat the average linear velocity of the beneficial agent through thepath is higher than that of the linear inward flux of materials from theenvironment of use due to diffusion or osmosis.

In reference to either of the osmotic delivery systems 140, 240, afterthe hole 124, 224 has been filled to a predetermined level with thebeneficial agent 144, 244, the stopper 170, 270 with the partition160,260 attached thereto in the manner described above, is inserted intothe hole 124, 224 capping or sealing the hole 124, 224 such that thebeneficial agent 144, 244 located within the delivery system 140, 240will not escape from the enclosure 142, 242 save from the deliveryorifice formed in the flow modulator body 121, 221.

The hole 124, 224 may be sized to accommodate the predetermined ratethat beneficial agent 144, 244 is delivered into the hole and toaccommodate any gas exiting the enclosure 142, 242 through the hole.Alternatively, the beneficial agent may be delivered into the enclosurewith a fill tube that is received by the hole, requiring that the hole124, 224 be larger than the diameter of the fill tube to accommodate theescaping gas. If the delivery rate of the beneficial agent 144, 244 isrelatively slow, the hole 124, 224 may have a smaller diameter and/or alonger length. If the predetermined rate of delivery of beneficial agent144, 244 into the hole 124, 224 is relatively fast, the hole 124, 244must have a larger diameter and/or a shorter length such that thebeneficial agent 144, 244 does not overflow the hole 124, 224 as it isdelivered through the hole. The level that the beneficial agent 144, 244reaches within the hole 124, 224 at the end of the filling process maybe selected such that when the stopper 170, 270 is inserted into thehole, little or no beneficial agent is expelled from the top of the hole124, 224 due to the stopper 170, 270 occupying a portion of the space ofthe fill hole 124, 224.

Alternatively, the beneficial agent 144, 244 may be forced into andthrough the hole 124, 224 such that gas or air is forced out of theenclosure 142, 242 through the delivery path 132, 232.

Because the flow modulator assembly 120, 220 forms a seal, except forthe delivery path 132, 232, with the interior surface 143, 243 of theenclosure 142, 242 the hole 124, 224 should be sufficiently large toaccommodate the rate of escaping air or gas from within the enclosure142, 242, which roughly equals the rate that the beneficial agent 144,244 is delivered into the fill hole 124, 224.

Assembling the osmotic delivery system 142, 242 in the above-describedmanner is advantageous because the amount of beneficial agent 144, 244which may be wasted is reduced. When the stopper 170, 270 is positionedwithin the flow modulator body 121, 221, only a minute amount of surplusbeneficial agent 144, 244 is expelled from the enclosure of the osmoticdelivery system 140, 240. This reduced amount of beneficial agent 144,244 expelled when assembling an osmotic delivery system 140, 240, ascompared to past assembly methods, reduces the cost of assembly. Becausethe amount of wasted beneficial agent is reduced, it is also easier todetermine the precise amount of beneficial agent 144, 244 remaining inthe osmotic delivery system 140, 240 for eventual delivery.

As described above, when delivering the beneficial agent 144, 244 intothe osmotic delivery system 140, 240, the hole 124, 224 permits gaswithin the enclosure of the osmotic delivery system to escape from thesystem. Thus, when the osmotic delivery system 140, 240 is completelyassembled, the amount of gas within the system is reduced. Thisreduction of trapped air or gas within the system is advantageousbecause the time to start-up of delivery of beneficial agent 144, 244from the delivery system to the environment of use is reduced.

When the osmotic delivery system 140, 240 is eventually placed into anenvironment of use, the osmotic agent 147, 247 imbibes fluid through thesemipermeable plug 148, 248 and expands, creating osmotic pressurewithin the enclosure 142, 242. This osmotic pressure forces thebeneficial agent 144, 244 through the delivery path 132, 232. Becausethe amount of gas or air within the enclosure 142 is reduced duringassembly of the osmotic delivery system, the osmotic agent 147, 247 neednot first compress air within the beneficial agent before forcing thebeneficial agent into the delivery path 132, 232. Hence, the start-upperiod to delivery of the beneficial agent 144, 244 is not delayed bythe amount of time which would ordinarily be necessary to compress airpockets within the osmotic delivery system 140, 240. Furthermore, thechance that significant amounts of air or gas may expel from the system,causing possible health risks, is reduced.

The check valve 141, 241 defined by the partition 160, 260 and a surfaceof the enclosure 142, 242 is advantageous because it reduces thepossibility of the inward flux of materials from the environment of useinto the osmotic delivery system 140, 240. That is, the check valve 141,241 reduces the chances of contaminants from entering the interior ofthe enclosure 142, 242, possibly destabilizing, diluting, or alteringthe beneficial agent formulation 144, 244. The check valve 141, 241permits the desired rate of beneficial agent 144, 244 to exit from theosmotic delivery system 140, 240, while also controlling the diffusionof liquids from the environment of use into the system. This is furtheradvantageous because the delivery path 132, 232 may be made larger suchthat it can accommodate difficult-to-deliver viscous or multi-phasedbeneficial agent formulations without a substantial risk of backdiffusion of substances into the osmotic delivery system 140, 240. Thus,the delivery path 132, 232 need not be sized such that the averagelinear velocity of the beneficial agent 144, 244 through the path ishigher than that of the linear inward flux of materials in theenvironment of use due to back diffusion because the check valve 141,241 substantially prevents liquids external of the osmotic deliverysystem from entering the osmotic delivery system.

A further advantage of the osmotic delivery system 140, 240 having theflow modulator assembly 120, 220 is that the system does not need to becapped to prevent evaporation of the beneficial agent 144 from thedelivery path 132, 232 of the system cause the partition 160 acts as acap or seal to prevent such evaporation. Accordingly, the osmoticdelivery system 140, 240 is simpler to manufacture than conventionalosmotic delivery systems while substantially preventing evaporation ofthe beneficial agent 144 from the system.

FIG. 9 illustrates that the hole 124 of the flow modulator body 121 mayalso be used in conjunction with a vacuum creating means 605, such as avacuum pump to further remove gas from the osmotic delivery system. Asshown in FIG. 9, the vacuum fixture 600 includes a first opening 608 forreceiving a delivery tube 508 of a beneficial agent delivery device 500.The vacuum fixture 600 also includes a second opening 604 for connectingthe interior of the vacuum fixture to the vacuum creating means 600.

The vacuum fixture 600 includes a third opening formed by the wall 602of the vacuum fixture which is sized and shaped to form a seal with theexterior surface of the enclosure 142 when the enclosure is received bythe third opening.

After the flow modulator body 121 has been inserted into the enclosure142, the third opening of the vacuum fixture 600 may be snugly pressedover the second opening of the enclosure 142 such that at least aportion of the enclosure is within the vacuum fixture 600. Thereafter,the delivery tube 508 is inserted into the first opening 608 and thevacuum means 606 is connected to the second opening 604. Preferably, thevacuum means 606 is initiated before any beneficial agent 144 isdelivered or inserted into the enclosure 142. The initiated vacuum means606 creates a vacuum adjacent to the flow modulator body 121, definingthe vacuum area 601 within vacuum fixture 600. For example, a vacuum ofapproximately 27 inches of mercury may be created by the vacuum means606. Hence, it is preferable that the first opening 608 form a seal withthe delivery tube 508 and that the wall 602 form a seal with theexterior surface of the enclosure 142.

Because a vacuum exists within the vacuum area 601, adjacent the flowmodulator body 121, the interior of the osmotic delivery systemenclosure 142 is also vented or evacuated via the hole 124 in the flowmodulator body 121 such that the amount of gas within the osmoticdelivery system is substantially reduced. After the gas has been removedfrom the osmotic delivery system 140 in the above-described manner, thebeneficial agent 144 is preferably delivered into the enclosure 142through the hole 124 in the flow modulator body 121 via the deliverytube 508 of the beneficial agent delivery device 500. Once thebeneficial agent 144 has been delivered into the enclosure 142 and hasat least partially filled the hole 124, the vacuum means may be shut-offand the vacuum fixture 600 removed from the enclosure. Thereafter, theassembly of the osmotic delivery system 140 may be completed byinserting the stopper 170 into the hole 124.

By creating a vacuum adjacent to the flow modulator body 121 beforedelivery of the beneficial agent 144 into the enclosure 142 and/or whileinserting the beneficial agent 144 through the hole 124, the amount ofgas within the osmotic delivery system is reduced. In addition, even ifa small amount of gas bubbles were somehow trapped within the enclosure142 of the osmotic delivery system 140, such gas bubbles will collapseafter the vacuum has been removed and the system is exposed toatmospheric pressure such that the collapsed bubbles dissolve into thebeneficial agent formulation 144. Hence, after the assembly of thedelivery system 140 is completed and the system is eventually placedinto an environment of use, the start-up period to delivery of thebeneficial agent 144 is not delayed by the amount of time ordinarilyrequired to compress gas pockets within the osmotic delivery system 140.

The above-described process may also be advantageously performed duringthe assembly of the osmotic delivery system 40 illustrated in FIG. 4. Itwill also be realized that other methods and apparatus may be used tocreate a vacuum adjacent to the flow modulator body 121 within theknowledge of those skilled in the art. For example, the vacuum may becreated by directly applying vacuum creating means to the hole 124 ofthe flow modulator body 121, rather than the enclosure 142.

The above description of the preferred and alternative embodiments ofthe present invention must be considered as illustrative only of theprinciple of the invention and not limitative. Indeed, it may be easilyunderstood that numerous modifications could be made by those skilled inthe art without departing from the spirit of the invention as defined inthe claims below.

We claim:
 1. An osmotic delivery system flow modulator assemblycomprising: an osmotic delivery system flow modulator body constructedand arranged for at least partial positioning in an opening of anenclosure of an osmotic delivery system, the body having two opposingends, a vent hole located through the body, the vent hole communicatingthe opposing ends, a delivery path formed in the body, located separatefrom the hole, and for controllably delivering a beneficial agent fromthe osmotic delivery system; a stopper at least partially positioned inthe vent hole; and a partition secured to the flow modulator body withthe stopper, wherein the stopper includes a shaft, a head, and a tiplocated opposite from the head, the partition being secured between theflow modulator body and the head of the stopper.
 2. An osmotic deliverysystem flow modulator assembly comprising: a flow modulator bodyconstructed and arranged for at least partial positioning in an openingof an enclosure of an osmotic delivery system, the body including twoopposing ends, a hole located through the body, communicating theopposing ends, and a delivery path for delivering a beneficial agentfrom an osmotic delivery system; a stopper having a head, a shaft, and atip located opposite from the head, the stopper being at least partiallypositioned in the hole to seal the hole; and a partition secured to thebody with the stopper so that the partition is secured between the bodyand the head of the stopper.
 3. A method of assembling an osmoticdelivery system having an enclosure, the enclosure having an opening,and the osmotic delivery system having a semipermeable portion, themethod comprising the steps of: positioning an osmotic agent in aninterior of the enclosure; inserting an osmotic delivery system flowmodulator body at least partially in the opening of the enclosure to atleast partially seal the opening, the flow modulator body constructedand arranged for at least partial positioning in an opening of anenclosure of an osmotic delivery system and including: two opposingends, a hole located through the body, the hole communicating theopposing ends, a delivery path for controllably delivering a beneficialagent from an osmotic delivery system, a stopper having a head, a shaft,and a tip located opposite from the head, the stopper being at leastpartially positioned in the hole, and a partition, the shaft beingpositioned through the partition so that at least a portion of thepartition is located between the head and the tip of the shaft; anddelivering a beneficial agent into the enclosure through the holethrough the flow modulator body.
 4. The method according to claim 3,further comprising the step of sealing the hole.
 5. The method accordingto claim 3, further comprising the step of venting the interior of theenclosure through an additional hole in the flow modulator body toreduce the amount of gas within the enclosure.
 6. The method accordingto claim 3, wherein the step of delivering of the beneficial agent intothe enclosure through the hole is achieved with one of a pipette and asyringe.
 7. The method according to claim 3, further comprising the stepof inserting a semipermeable plug into a second opening of theenclosure.
 8. The method according to claim 5, further comprising thestep of sealing the additional hole.
 9. The method according to claim 4,wherein the hole is sealed with a cap.
 10. The method according to claim3, further comprising the step of venting the interior of the enclosurethrough the hole in the flow modulator body while delivering thebeneficial agent into the enclosure to reduce an amount of gas withinthe enclosure.
 11. A method of delivering a beneficial agent into anosmotic delivery system, comprising the steps of: inserting thebeneficial agent through a hole in a flow modulator body inserted in anopening of the osmotic delivery system, the flow modulator bodyconstructed and arranged for at least partial positioning in an openingof an enclosure of an osmotic delivery system and including: twoopposing ends, a hole located through the body, the hole communicatingthe opposing ends, a delivery path for controllably delivering abeneficial agent from an osmotic delivery system, a stopper having ahead, a shaft, and a tip located opposite from the head, the stopperbeing at least partially positioned in the hole, and a partition, theshaft being positioned through the partition so that at least a portionof the partition is located between the head and the tip of the shaft;and venting gas from the osmotic delivery system through the hole whileinserting the beneficial agent through the hole.
 12. The methodaccording to claim 11, further comprising the step of creating a vacuumadjacent to the flow modulator body to reduce an amount of gas withinthe osmotic delivery system.
 13. The method according to claim 11,further comprising the step of sealing an interior of the hole from asurrounding environment.
 14. A method of assembling an osmotic deliverysystem having an enclosure, the enclosure having an opening, and theosmotic delivery system having a semipermeable portion, comprising thesteps of: positioning an osmotic agent into an interior of theenclosure; inserting an osmotic delivery system flow modulator body atleast partially in the opening of the enclosure, the flow modulator bodyconstructed and arranged for at least partial positioning in an openingof an enclosure of an osmotic delivery system and including: twoopposing ends, a hole located through the body, the hole communicatingthe opposing ends, a delivery path for controllably delivering abeneficial agent from an osmotic delivery system, a stopper having ahead, a shaft, and a tip located opposite from the head, the stopperbeing at least partially positioned in the hole, and a partition, theshaft being positioned through the partition so that at least a portionof the partition is located between the head and the tip of the shaft;delivering a beneficial agent into the enclosure through the holethrough the flow modulator body; and creating a vacuum adjacent to theflow modulator body to reduce an amount of gas within the osmoticdelivery system.
 15. The method according to claim 14, furthercomprising the step of sealing the hole.
 16. The method according toclaim 15, wherein the hole is sealed with a stopper.
 17. The methodaccording to claim 14, further comprising the step of attaching to theinserted flow modulator body means for preventing a liquid external ofthe osmotic delivery system from entering the interior of the osmoticdelivery system, the preventing means allowing the beneficial agent toexit the osmotic delivery system to a surrounding environment.